1. Field of the Invention
We have now discovered a new method that can be used to safely and effectively cleanse a patient's bowels, especially the colon prior to diagnostic or surgical procedures.
2. Background Information
Although years of clinical research have been expended to make early detection of colorectal cancer (CRC) a high clinical priority, the disease remains the second leading cause of cancer-related death in the United States. In 1999, an estimated 60,000 deaths were attributed to CRC which accounted for the third highest number of new cancer cases that year, only lagging prostate and respiratory cancers for men and breast and respiratory cancers in women. Investigators estimate there were 129,000 new cases in 1999 alone. Lifetime risk for developing CRC is therefore 1 case per 18 people in the United States.
Despite the success of screening procedures which can reduce the rate of death by detecting early cancer or premalignant polyps, only about 30% of eligible patients are screened. Reasons given for this low rate of screening include physicians', patients' and health care providers' reluctance to encourage, receive, or pay for these procedures. This has been recognized most recently at the Federal level on Jul. 10, 2002 when a U.S. Senate committee voted to require all private health insurance plans in the United States to provide coverage for colonoscopies and other tests to detect colon cancer in people who are 50 or older or have a high risk of developing the disease.
Patients who are undergoing surgical procedures or diagnostic examinations of the large bowel usually undergo preparation to assure that the bowel is cleansed of all fecal material adequately before the procedure. This serves to minimize contaminating the operating area for example, during surgery for explorations of potential masses or for bowel resection. An additional purpose is to allow a clean interior surface of the colon for diagnostic examination, for example during endoscopic surveillance as a diagnostic examination for detecting colon cancer.
In sigmoidoscopy, colonoscopy, radiographic examination, preparation for patients undergoing bowel surgery, and other medical or diagnostic procedures on the bowels or colon, it is important that the bowels and colon be thoroughly purged and cleaned. In particular, it is essential that as much fecal matter as possible be removed from the colon to permit adequate visualization of the intestinal mucosa. This is important prior to, for example, diagnostic procedures such as flexible sigmoidoscopy or colonoscopy, diagnostic examinations widely performed to screen patients for diseases of the colon. In addition, it is important that the intestines be cleansed thoroughly in order to obtain satisfactory radiographs of the colon. The same condition also applies when the colon is preoperatively prepared for surgery, where removal of fecal waste materials is critically important for patient safety.
Among the procedures for CRC detection, controversy over which is the most cost effective continues, but most practitioners today agree that colonoscopy detects the highest rate of cancers and affords simultaneously the opportunity for their endoscopic removal. To prepare the colon for endoscopic exam, current cleaning procedures include the combination of reduced food intake with laxatives, enemas, suppositories, bowel evacuants, or orthograde colonic lavage. Orthograde lavage with Polyethylene Glycol/Electrolyte Solutions (PEG-ELS, GoLYTELY® or SF-ELS, NuLYTELY®) is a frequently prescribed preparation. These “preps”, consisting of 4 L of solution, are generally uncomfortable for the patient to complete. They often complain of a sense of fullness, nausea, cramping, and vomiting, sometimes of such magnitude that they do not complete the prescribed regimen. Failure to complete the regimen is a frequently named cause of inadequate bowel cleansing which often results in termination of the colonoscopy. One way to improve the patients' willingness to undergo and complete colonoscopy would be to reduce the volume of lavage solution.
Physicians and surgeons have developed a variety of means to achieve the desired level of colon cleansing. The use of dietary restrictions, laxatives, enemas, and whole-bowel lavage solutions, alone or together, has been employed. Two components of this bowel-cleansing procedure, namely, a clean colon to assist the medical procedure, and safe, easy to take and pleasant “patient friendly” colon-cleaning procedure, have not been simultaneously attainable in present medical practice. What the physician may find to provide the “cleanest” colon may require multiple days of fasting, laxative use and large volume liquid ingestion by the patient. What the patient perceives as the most comfortable preparation regimen may not yield an adequately cleansed colon. In many cases, patients do not comply with preparation regimens that the patients feel are too inconvenient or too uncomfortable. In addition, many preparations may pose a health risk, as they cause fluid and electrolyte disturbances in the body, which are known to be harmful, even deadly, in some patients. The variety of methods now used for colonic evacuation is a testament to the lack of an ideal means to achieve its goals. What is needed is a procedure that is both highly efficacious and safe, while at the same time is tolerable to the patient, to encourage compliance for frequent examinations.
Large volume orally administered compositions have been developed for use as gastrointestinal washes for diagnostic purposes or for use as cathartic laxatives. Such orally administered preparations are usually formulated as dilute or isotonic solutions of electrolytes such as sodium sulfate, sodium bicarbonate, sodium chloride and potassium chloride. These orally administered compositions are useful in the rapid cleansing of the colon for diagnostic purposes. These formulations may include other agents such as polyethylene glycol. These formulations have generally been administered in a quantity of about four liters as isotonic solutions. One example composition is GoLYTELY® formulated, in one liter of water, according to the following: polyethylene glycol 59 g, sodium sulfate 5.68 g, sodium bicarbonate 1.69 g, sodium chloride 1.46 g, potassium chloride 0.745 g (Davis et al. Gastroenterology 1980; 78: 991-995).
Commercially available products embodying these formulations sometimes utilize polyethylene glycol, a non-absorbable osmotic agent, with an isotonic mixture of electrolytes for replenishment, so that patients do not become dehydrated or experience clinically significant electrolyte shifts. Because the solutions are isotonic, patients are required to ingest a significant amount of volume of these solutions, up to one eight ounce glass every ten minutes for a total of one gallon of fluid, to achieve effective purging.
The large volume required for effective use of this type of formulation for lavage is frequently associated with distention, nausea, cramping, vomiting, and significant patient discomfort. Thus, while these formulations are generally effective, they are not well tolerated. Without close supervision, many patients do not take the complete course of preparation.
Sodium sulfate and phosphate salts have been used as laxatives when diluted in a small volume (˜300 ml) concentrated solution and taken in tablespoon sized (15 ml) daily doses. An example of this use is Glauber's Salt's (containing sodium sulfate). However, because of their small volumes, when used in this fashion they do not sufficiently clean the colon for diagnostic or surgical procedures. Also these small volume preparations do not contain polyethylene glycol. Sodium sulfate combined with polyethylene glycol and various other salts, administered in large volumes (1 gallon) over a short period of time is an effective gastrointestinal lavage, which cleanses the colon prior to colonoscopy or surgical procedures as described above.
Another drawback of these prior art preparations is their unpleasant, bitter, saline taste. This can promote nausea and vomiting in sensitive patients—thereby preventing ingestion. It is difficult to overcome this unpleasant taste, even the most common natural sweeteners such as glucose, fructose, saccharose, and sorbitol could change the osmolarity of these orally administered solutions resulting in potentially dangerous electrolyte imbalances.
In an attempt to avoid the problems associated with the high volume types of preparations, other investigators have utilized ingestible preparations that consist of aqueous solutions of concentrated phosphate salts. The aqueous phosphate salt concentrate produces a tremendous osmotic effect on the intra-luminal contents of the bowel and therefore, evacuation of the bowel occurs with a large influx of water and electrolytes into the colon from the body. These phosphate salt preparations have been developed for the purpose of decreasing the volume required in colonic purgations. One such preparation basically is comprised of 480 grams per liter monobasic sodium phosphate and 180 grams per liter dibasic sodium phosphate in stabilized buffered aqueous solution and is sold under the brand name Fleets Phospho-Soda®. Patients are typically required to take two (2) three ounce doses of this preparation, separated by a three to 12 hour interval for a total of six ounces (180 ml), which is a significant reduction compared to the large 1 gallon volumes required by the high volume preparations. Additionally, non-aqueous tablet or capsule formulations of sodium phosphates and sulfates have been used (U.S. Pat. Nos. 5,997,906, 6,162,464, and 5,616,346).
These small volume sulfate/phosphate solutions and non-aqueous formulations have been shown to cause massive electrolyte and fluid shifts that are clinically significant to the patient (US Food and Drug Administration, Center for Drug Evaluation and Research, Sep. 17, 2001; 2002 Physician's Desk Reference, prescribing information for Fleet's Phospho Soda and InKine Pharmaceutical's Visicol®). The terms “clinically significant” as used herein are meant to convey alterations in blood chemistry that are outside the normal upper or lower limits of their normal range or other untoward effects. These solutions are hyperosmotic; that is the electrolyte concentration of the solution is much higher than the electrolyte concentration in the human body. Available products, as Fleet's Phospho-Soda, and the solid dosage form such as Visicol tablets (sodium phosphate salts) are examples of small volume electrolyte preparations. All of these products have been seen to cause clinically significant electrolyte disturbances and fluid shifts, and disturbances in cardiac and renal function when administered to patients (US Food and Drug Administration, Center for Drug Evaluation and Research, Sep. 17, 2001).
To overcome the risks and electrolyte disturbances that occur with the small volume laxative preparations, large volume “lavage” solutions were developed to be isotonic. Preparing a patient for a surgical or diagnostic procedure on the colon with such an isotonic lavage would result in only minimal fluid and electrolyte shifts in the patient. GOLYTELY®, NULYTELY®, and CoLyte® are examples of such large volume lavages. Because these lavages are isotonic, the patient experiences minimal, non-clinically significant fluid and electrolyte shifts, if any, upon their administration.
Davis and Fordtran (Gastroenterology 78:991-5, 1980) developed a four-liter polyethylene glycol and electrolyte bowel lavage solution (GoLYTELY), which has been shown to be safe and effective as a means of rapidly evacuating the colon in preparation for colonoscopy, barium enema and surgery. When ingested it produces a voluminous, liquid stool with minimal changes in the patient's water and electrolyte balance. As such, lavage solutions are often referred to as the “gold standard” by physicians who wish their patients to achieve the cleanest colon. Although, the formula for this drug was modified to improve the flavor of the solution, many patients have expressed a dislike for the large volumes that must be ingested. Indeed, many of the labeled adverse reactions typical of this kind of preparation (such as nausea and vomiting) can be attributed to a volume effect. Ideally, one would want to somehow reduce the dose, thereby increasing patient comfort, without compromising the quality of bowel cleansing.
Clinical studies spanning over 20 years have attempted to reduce the volume of PEG based lavage preparations by combining them with laxatives, most notably bisacodyl. In many of these initial attempts, the volume of the solution was maintained at 4L, even with the addition of bisacodyl. In other experiments, attempts were made to use smaller volumes of a PEG based solution without bisacodyl or a laxative. Generally, these attempts produced improved patient symptoms but reduced the quality of the colonoscopy below acceptable standards. Vilien and Rytkonen (Endoscopy 22:168-170, 1999) published a study of 50 patients that compared a reduced volume GoLYTELY regimen with their standard GoLYTELY preparation for colonoscopy. Colonoscopists who were unaware of the cleansing regimen that the patients had received rated the cleansing efficacy. On the day before examination, all patients were given 10 mg bisacodyl followed by a liquid diet. Then, on the morning of the exam, patients drank either 1.5 or 3 liters of GoLYTELY (depending upon the randomization schedule). The authors concluded that there was less complete cleansing when the lower lavage volume was used. However, it is not clear how well these two treatments cleansed the bowel in comparison to the standard 4 liters of lavage solution alone.
Other authors have tried to combine colon-cleansing modalities to achieve a clean, well-tolerated, preparation. Adams et al. (Dis. Colon Rectum 37:229-234, 1994) compared preparation with bisacodyl followed eight hours later by 2 liters of GoLYTELY to the “standard” four liters of GoLYTELY. These authors found that when patients received the bisacodyl 28-30 hours before examination and were placed on a clear liquid diet for more than 30 hours before examination, the quality of bowel cleansing between the two preparations appeared to be equivalent but the bisacodyl plus 2 liters GoLYTELY method was better tolerated. However, patients who received the bisacodyl plus 2 liters of GoLYTELY, but were not restricted to liquids for more than 30 hours before examination, did not have satisfactory preparation.
In a similar study, of patients scheduled for colon surgery, the results of colon cleansing were judged to be of the same visual quality, but the patients did not find any improvement in their level of discomfort (Grundel K, Schwenk W., Bohm B, and Muller J M, Dis Colon Rectum 1997 Nov; 40(11): 1348-52).
Other studies have failed to find a good combination of physician and patient assessments when a laxative is used in conjunction with a reduced lavage volume. Indeed, Bokemeyer (Verdauungskrankheiten, 18:17-24, 2000) found that the laxative plus reduced lavage volume resulted in “Colonoscopy preparation with a smaller volume of PEG-lavage solution in combination with a laxative (X-Prep) produced significantly worse results.” See also the work of Lind and Wiig (Tidsskr Nor Laegeforen 110:1357-1358, 1990) and of Brady and others (Ann Clin Research 19:34-38, 1987) for other failed attempts.
An alternative approach, the dosing of the patient with a laxative after the administration of a lavage has been tried and found to produce no improvement in patient symptoms over administering the full lavage volume (Clarkston and Smith J. Clin Gastroenterology 17:146-148, 1993).
Finally, the simultaneous co-administration of laxatives with a reduced volume of PEG-ELS produced cleansing similar to 4L of PEG-ELS alone and reduced patient symptoms, but, the patients were also pretreated with simethicone, an anti-gas medication (Sharma et al., Gastrointestinal Endoscopy, 47(2):167-71, 1998).
Thus, despite others' attempts, improved patient symptoms do not necessarily follow the use of reduced volumes of lavage fluids with laxative pretreatment. Nor does the combination reliably produce a colon preparation that is as good as that achieved when a large volume lavage solution is used.
Furthermore, the attempts to cleanse the colon with a smaller volume of a lavage solution in combination with a laxative have made the patients and physicians engage in protracted fasting and a cumbersome schedule for the preparation. For example, Grundel et al required their patients to consume clear liquids and soup for two days before the surgery, so it is perhaps not surprising that they achieved good colon clean-out with a minimal volume lavage. Adams required patients consume only clear liquids for 28-32 hours before examination.
As noted above, what we have found is that prior attempts to obtain at the same time both an adequate preparation and improved patient comfort have failed because they overlooked key parameters in the dosing of the patients, namely, the duration of time between laxative and lavage ingestion and the effect of the laxative prior to the lavage. Adams required patients consume only clear liquids for 28-30 hours before examination.
From the foregoing, it can be seen that the two approaches to colonic lavage that have been used in the past have significant drawbacks that have not been resolved by prior attempts. The isotonic solutions, while not causing clinically significant fluid or electrolyte shifts, are, of necessity, of large volume, and difficult for patient ingestion. The hypertonic solutions or concentrated non-aqueous formulations are sometimes inadequate to prepare the colon and more importantly, can cause clinically significant electrolyte and fluid shifts, which have been known to cause deaths. Thus, it is desirable to have a small volume orally administered colonic purgative formulation which may be easily and conveniently administered and which avoids the clinically significant problems and objectionable tastes of known formulations. It can also be seen that it is desirable to have such a purgative formulation which may be administered without the large volumes necessary in conventional formulations and which avoids other potentially irritant chemicals or chemicals which could effect osmolarity. In the nearly 20 years since the advent of large volume colonic lavage solutions, there has not been success in discovering an effective small volume gastrointestinal cleansing preparation that minimized fluid or electrolyte shifts. Concentrating the large volume lavages into smaller volumes does not achieve the same effectiveness, and is not as safe. This is because the components are not soluble in the small volumes necessary and because the concentrations are such that dangerous electrolyte shifts could occur. One purpose of the present research was to develop a safe, effective, and well tolerated method of cleansing a colon that required a small volume of solution.
Available methods for cleansing a colon are not optimally tolerated by patients, and have potentially dangerous side effects. We have now found that administering a reduced volume of a solution containing an osmotic laxative, such as polyethylene glycol in conjunction with a stimulant laxative, can achieve safe and effective cleansing of the colon prior to diagnostic or surgical procedures.